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Regulatory crosstalk and interference between the PCB 126 stimulated AHR and hypoxia stimulated HIF-1α signaling pathwaysVorrink, Sabine Ulrike 01 May 2014 (has links)
Polychlorinated biphenyls (PCBs) are synthetic organic chemicals that persist in the environment and are known to be carcinogenic to humans. Virtually all of the deleterious effects of PCB 126, the most potent dioxin-like PCB, are mediated by the aryl hydrocarbon receptor (AhR). By means of the common cofactor ARNT, the AhR signaling pathway can crosstalk with the hypoxia signaling pathway. Regulated by hypoxia-inducible factors (HIFs), the hypoxia pathway mediates responses to environments of reduced oxygen availability (hypoxia). This dissertation specifically examines the crosstalk and interference between these two pathways in the context of PCB 126 exposure. The results of this dissertation show that the antagonistic relationship between the AhR and hypoxia signaling pathways affects the function and responses of both AhR and HIF-1Α. We provide substantial evidence that ARNT is indeed a crucial factor in both the AhR and HIF-1Α signaling pathways. Furthermore, this dissertation examines regulatory mechanisms involved in AhR-mediated gene expression and identifies epigenetic regulation as a critical factor in AhR target gene expression. In summary, this dissertation helped to improve the understanding of mechanisms of PCB 126 toxicity. Understanding the detrimental biological effects of these ubiquitous environmental pollutants might ultimately have significant implications for human health.
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ACTIVIN B PROMOTES HEPATIC FIBROGENESISYan Wang (7022162) 16 October 2019 (has links)
<p>Activin
B, a TGFβ ligand, is associated with liver inflammatory response. We aimed to
investigate whether it modulates liver fibrogenesis. <b> </b>Liver and
serum activin B, along with its analog activin A, were analyzed in patients
with liver fibrosis from different etiologies and in mouse acute liver injury
and liver fibrosis models. Activin B, activin A, or both was immunologically
neutralized in progressive or established carbon tetrachloride-induced mouse
liver fibrosis. The direct effects of activin B and A on hepatocytes,
macrophages, and hepatic stellate cells (HSCs) were evaluated <i>in vitro</i>. In human patients, increased activin B is associated with liver
fibrosis irrespective of the etiologies. In mice, activin B exhibited
persistent elevation in liver and circulation following the onset of liver
injury, whereas activin A displayed transient increases. Neutralizing activin B
largely prevented and remarkably regressed liver fibrosis, which was augmented
by co-neutralizing activin A in mice. Mechanistically, activin B promoted
hepatocyte injury, activated macrophages to release cytokines, and induced a
pro-fibrotic expression profile and septa formation in HSCs, which were
magnified by activin A. Furthermore, activin B and A interdependently activated
the CXCL1/iNOS pathway in macrophages and additively upregulated CTGF
transcript in HSCs <i>in vitro</i>. Consistently, the expression of these genes
was prohibited by neutralizing either one of these two ligands in injured
livers. Activin B potently drives the initiation and progression of
liver fibrogenesis. It additively or interdependently cooperates with activin
A, directly acts on multiple liver cell populations, and induces liver
fibrogenesis.<b> </b>Antagonizing activin B or both activins B and A prevents
and regresses liver fibrosis in mouse CCl<sub>4</sub> model, inspiring the
development of a novel therapy of chronic liver diseases.</p>
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Energetic Costs of AhR Activation in Rainbow Trout (Oncorhynchus mykiss) HepatocytesNault, Rance 22 September 2011 (has links)
Aquatic organisms in response to toxic insults from environmental pollutants activate defence systems including the aryl hydrocarbon receptor (AhR) in an attempt to metabolize and excrete these toxicants and their metabolites. These detoxification mechanisms however may come with certain energetic costs. I hypothesize that the activation of the AhR by β-Naphthoflavone (β-NF), a model AhR agonist, results in increased energetic costs requiring metabolic reorganization in rainbow trout hepatocytes. While the results obtained suggest that there are no significant energetic costs of AhR activation, analysis of enzyme activities suggests possible metabolic reorganization. This study also showed significant changes in cellular processes in hepatocytes over the incubation periods which previously were not reported. Furthermore, for the first time in fish hepatocytes, metabolic flux analysis (MFA) was used to examine intra-cellular metabolism, the applicability of which is discussed.
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Energetic Costs of AhR Activation in Rainbow Trout (Oncorhynchus mykiss) HepatocytesNault, Rance 22 September 2011 (has links)
Aquatic organisms in response to toxic insults from environmental pollutants activate defence systems including the aryl hydrocarbon receptor (AhR) in an attempt to metabolize and excrete these toxicants and their metabolites. These detoxification mechanisms however may come with certain energetic costs. I hypothesize that the activation of the AhR by β-Naphthoflavone (β-NF), a model AhR agonist, results in increased energetic costs requiring metabolic reorganization in rainbow trout hepatocytes. While the results obtained suggest that there are no significant energetic costs of AhR activation, analysis of enzyme activities suggests possible metabolic reorganization. This study also showed significant changes in cellular processes in hepatocytes over the incubation periods which previously were not reported. Furthermore, for the first time in fish hepatocytes, metabolic flux analysis (MFA) was used to examine intra-cellular metabolism, the applicability of which is discussed.
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Investigation on the Pathological Role of Hepatoma-Derived Growth Factor in Hepatic FibrogenesisKao, Ying-hsien 25 August 2009 (has links)
Liver fibrosis, a major medical problem with significant morbidity and
mortality, is considered as a wound-healing response to a variety of chronic
stimuli. It is characterized by an excessive deposition of extracellular
matrix (ECM) proteins, which disrupts the normal architecture of liver and
ultimately leads to pathophysiological damage to liver. Hepatoma-derived
growth factor (HDGF), a growth factor originally purified from hepatoma
cells, is highly expressed in fetal hepatocytes and hepatoma. It is known to
play multifunctional roles in mitogenesis, organogenesis, embryogenesis,
and tumorigenesis. Its expression correlates with the proliferating state of
hepatocellular carcinoma (HCC) and serves as a prognostic factor. Since
liver fibrosis frequently occurs prior to HCC development, the specific aim
of this study is to investigate the role of HDGF in the progression of liver
fibrosis by using animal models of mice receiving either bile duct ligation
surgery or carbon tetrachloride administration. Quantitative real-time PCR
and Western blotting analysis showed a significant elevation of HDGF
expression in both models. HDGF levels correlated with progression of
liver fibrosis in a time-dependent manner as well as paralleled with the
expression of other two fibrotic markers, transforming growth factor-b1
(TGF-b1) and pro-collagen type I, in fibrotic livers. Intriguingly, the
over-expressed HDGF protein was localized mainly in perivenous
hepatocytes of fibrotic livers. Besides, adenovirus-mediated HDGF gene
delivery potentiated the production of TGF-b1 and pro-collagen type I,
thereby enhancing the intrahepatic collagen matrix deposits as evidenced
by Sirius red stain and morphometrical analysis. In cultured hepatocytes,
TGF-b1 and HDGF mutually up-regulated their de novo synthesis only
when grown on collagen-coated matrix, strongly suggesting that the
TGF-b1- and/or HDGF-driven pro-fibrogenic signaling is
collagen-dependent and a vicious circle may exist at the initial stage of
hepatic fibrogenesis. Moreover, administration with recombinant HDGF
stimulated BrdU uptake and synthesis of both a-smooth muscle actin and
pro-collagen type I in cultured hepatic stellate cells, implicating that a
mode of paracrinal action lies between these two cell types. In conclusion,
HDGF plays a pro-fibrogenic role during liver fibrosis and blockade of
HDGF pathway may potentially constitute the preventive or therapeutic
strategies for chronic liver diseases.
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Pro- and anti-apoptotic roles of map kinase signaling in liver exposed to alcohol /Lee, Youn Ju, January 2003 (has links)
Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / "December 2003." Typescript. Vita. Includes bibliographical references (leaves 172-205). Also issued on the Internet.
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Hipertermijos poveikis adenino ir piridino nukleotidų koncentracijai kepenų ląstelėse ir audinyje / The effect of hyperthermia on the concentration of adenine and pyridine nucleotides in hepatocytes and liver tissueKirvelaitytė, Dovilė 14 June 2010 (has links)
Šilumos taikymas įvairioms ligoms gydyti jau buvo naudojamas senovės Egipto, Graikijos, Romos civilizacijose daugiau kaip prieš 2000 m. pr. Šiuo metu hipertermija plačiai taikoma visame pasaulyje gydant vėžį, nes tai pigus ir patogus metodas turintis mažą šalutinį poveikį. Mokslininkai nustatė, kad vėžinės ląstelės greičiau žūsta esant aukštesnei už fiziologinę (41-45°C) temperatūrai, todėl hipertermija, derinama su kitais vėžio gydymo metodais (radioterapija, chemoterapija, imunoterapija ir chirurgija), tampa efektyvesniu metodu. Kadangi yra mažai žinoma apie hipertermijos poveikio mechanizmą sveiko audinio ląstelėms karščiavimo, hiperterminio vėžio gydymo ar gydymo termoabliacija metu, todėl yra svarbu nustatyti hipertermijos paveiktų ląstelių gyvybingumą bei hipertermijos poveikį adenino ir piridino nukleotidų koncentracijoms. Šio darbo tikslas buvo įvertinti hipertermijos, būdingos nutolusioms nuo termozondo audinio sritims poveikį, adenino ir piridino nukleotidų koncentracijoms žiurkės kepenų ląstelėse bei audinyje. Buvo naudojamas jonų porų efektyviosios skysčių chromatografijos metodas, leidžiantis vienoje chromatografinėje analizėje išskirstyti labai skirtingo hidrofobiškumo junginius. Taip pat buvo vertintas gyvų ir negyvų ląstelių skaičius gautoje hepatocitų suspensijoje panaudojant tripano mėlio metodą bei NAD(P)H fluorescencijos pokyčiai kepenų audinyje termoabliacijos metu. Gauti rezultatai parodė, kad išskirti hepatocitai pasižymėjo dideliu gyvybingumu (8... [toliau žr. visą tekstą] / The application of heat in the treatment of disease was first recorded in the ancient civilizations of Egypt, Greece, and Rome from as early as 2000 BC. Nowadays hiperthermia is widely using in cancer diseases in all the world. It was determined by many scientists that cancer cells are more sensitive for supraphysiological temperature (41-45°C) killing compared to normal cells. There are numerous evidences that hyperthermia can increase the effectiveness of other cancer therapies: radiotherapy, chemotherapy, immunotherapy and surgery. There is little known about the mechanisms of hyperthermia effects on healthy tissue, which are important in fever, in hyperthermic treatment of neighboring tumour and in thermoablation. Therefore it is very important to determinate the vability of cells during different hyperthermic treatment and hyperthermic effects of adenine ir pyridine nucleotides concentrations.The aim of study was to value the effect of hyperthermia,which is typical remote from thermoprobe tissue areas, on the concentration of adenine and pyridine nucleotides in hepatocytes and liver tissue. It was used ion-pair high-performance liquid chromatography method, which allows to disperse different combinations of hydrophobicity. Also were evaluated live and dead cells quantity in the suspension through tripan blue method and NAD(P)H fluorescence changes in liver tissue during the ablation. The results showed that isolated hepatocytes exhibited with high viability (80%)... [to full text]
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Characterization of Phosphatidylcholine Metabolism in Mouse Hepatocytes after Hepatectomy and in Primary Human HepatocytesLing, Ji Unknown Date
No description available.
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Role of triacylglycerol hydrolase in hepatic lipid droplet metabolismWang, Huajin Unknown Date
No description available.
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Regulation of Cholesterol Biosynthesis in HepatocytesEnns, Jennifer Emily 23 August 2010 (has links)
Hypercholesterolemia, a condition of high cholesterol levels in the circulation, poses a major risk for developing cardiovascular disease, such as atherosclerosis. A common method of reducing plasma cholesterol levels relies on the administration of drugs that limit cholesterol synthesis or uptake, many of which have undesirable side effects. Thus, some patients are turning to an alternative treatment, namely natural health products. Natural health products are often equally or even more effective at treating illness than synthetic drugs and may produce fewer side effects. The goal of this study was to identify a natural health product that regulates hepatic cholesterol synthesis by inhibiting HMG-CoA reductase, the enzyme which catalyzes the rate-limiting step of the cholesterol synthesis pathway. Several natural compounds were screened using the human hepatoma cell line HepG2. One compound, berberine, showed great potential as a regulator of cholesterol synthesis and so became the subject of this investigation. Berberine inhibited HMG-CoA reductase activity and decreased cellular accumulation of cholesterol. Berberine was shown to regulate HMG-CoA reductase through activation of metabolic regulator AMP-activated protein kinase, which modifies HMG-CoA reductase post-translationally and thereby decreases its activity. In conclusion, this study demonstrates that the natural health product berberine decreases cholesterol synthesis by activating a cellular signalling pathway to bring about post-translational modification of HMG-CoA reductase, and in doing so, inhibits this enzyme. This novel mechanism supports berberine’s potential for a cholesterol-lowering therapy and its role in reducing the risk for cardiovascular disease.
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